Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
  • C07D213/18—Salts thereof

Definitions

• Salts of substituted nitrogen heteroaromatic compounds process for their preparation and pharmaceutical compositions containing them.
• the subject of the present invention is new salts of substituted nitrogenous heteroaromatic compounds, a process for their preparation and the pharmaceutical compositions containing them as active principles.
• the present invention relates to a new class of substituted nitrogen heteroaromatic compound salts for therapeutic use, in pathological phenomena which involve the tachykinin system, for example in a non-limiting and exclusive manner: pain (D. Regoli et al. , Life Sciences, 1987, 40, 109-117), allergy and inflammation (JE Morlay et al., Life Sciences, 1987, 41, 527-544), circulatory failure (J. Losay et al. , 1977, Substance P, Von Euler, IS and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484 ), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), neurological disorders, neuropsychiatric disorders (CA Maggi et al., J. AutonomiePharm acol., 1993, 13, 23- 93).
• pain D. Regoli et al
• Tachykinins are distributed in both the central nervous system and the peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK 1 , NK 2 , NK 3 .
• Substance P is the endogenous ligand for NK 1 receptors, neurokinin A (NKA) for NK 2 receptors and neurokinin B (NK ⁇ ) for NK 3 receptors.
• NK 1 , NK 2 , NK 3 receptors have been demonstrated in different species.
• a review by CA Maggi et al. takes stock of tachykinin receptors and their antagonists and explains pharmacological studies and applications in human therapy (J. Autonomie Pharmacol., 1993, 13, 23-93).
• NK 1 receptor specific antagonists the following non-peptide compounds may be mentioned: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA , 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
• SR 48968 a selective non-peptide antagonist, SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
• certain non-peptide compounds have been described as having an affinity for the NK 3 receptor of the rat and guinea pig brain (FASEB J., 1993, 7 (4), A710, 4104); a peptide antagonist [Trp 7 , ⁇
• NK A poorly specific for the NK 3 receptor of the rat brain has also been described (J. Autonomie. Pharmacol., 1993, 13, 23-93).
• Patent application EP-A-336230 describes peptide derivative antagonists of substance P and of neurokinin A useful for the treatment and prevention of asthma.
• EP-A-0474561, EP-A-512901, EP-A-515240, EP-A-559538 and EP-A-591040 also relate to neurokinin receptor antagonists.
• Novel salts of substituted nitrogen heteroaromatic compounds have now been found which are neurokinin receptor antagonists.
• the present invention relates to compounds of formula:
• - Ar represents an aromatic or heteroaromatic mono-, di- or tricyciic group optionally substituted
• - T represents a direct bond; a hydroxymethylene group; an (C 1 -C 4 ) alkoxymethylene group; a (C 1 -C 5 ) alkylene group; an oxygen atom; a group -NR 3 -; vinylene;
• - Ar represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a trifluoromethyl, a hydroxy, a (C 1 -C 4 ) alkoxy, a (C 1 -C 4 ) alkyl, said substituents being identical or different; thienyl; benzothienyl; naphthyl; an indolyl optionally N-substituted by a (C 1 -C 4 ) alkyl or a benzyl;
• R 1 represents a hydrogen; a (C 1 -C 4 ) alkyl; ⁇ -hydroxy- (C 2 - C 4 ) alkylene; ⁇ - (C 1 -C 4 ) alkoxy- (C 2 -C 4 ) alkylene; ⁇ -benzyloxy- (C 2 -C 4 ) alkylene; ⁇ -formyloxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 - C 4 ) alkylcarbonyloxy- (C 2 -C 4 ) alkylene; a ⁇ -benzoyloxy- (C 2 -C 4 ) alkylene; ⁇ -R 6 NHCOO- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkylthio- (C 2 -C 4 ) alkylene; ⁇ -carboxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1
• R 1 and R 2 together, form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
• R 3 represents a hydrogen or a (C 1 -C 4 ) alkyl
• R 4 represents a group
• - W represents a direct bond; a methylene group; an oxygen atom; a sulfur atom; a group -NR 3 -;
• R 5 represents a hydrogen; halogen; hydroxy; a (C 1 - C 4 ) alkoxy; a (C 1 -C 4 ) alkyl; trifluoromethyl;
• R 6 represents a (C 1 -C 7 ) alkyl or a phenyl
• - R 7 and R 8 each independently represent a hydrogen or a (C 1 -C 7 ) alkyl
• R 8 may also represent a (C 3 -C 7 ) cycloalkyl, a (C 3 -C 7 ) cycloalkylmethyl, a phenyl or a benzyl;
• R 7 and R 8 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine;
• R 9 and R 10 each independently represent a hydrogen or a (C 1 -C 7 ) alkyl; R 10 may also represent a (C 3 -C 7 ) cycloalkylmethyl or a benzyl;
• R 11 represents a hydrogen, a (C 1 -C 7 ) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C 3 -C 7 ) cycloalkyl unsubstituted or substituted by one or more methyls;
• R 12 represents a hydrogen or a (C 1 -C 7 ) alkyl
• R 13 represents a (C 1 -C 7 ) alkyl or a phenyl
• R 14 represents a (C 1 -C 7 ) alkyl; an amino free or substituted with one or two (C 1 -C 7 ) alkyls; a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a (C 1 -C 7 ) alkyl, a trifluoromethyl, a hydroxy, a (C 1 -C 7 ) alkoxy, a carboxy , a (C 1 - C 7 ) alkoxycarbonyl, a (C 1 -C 7 ) alkylcarbonyloxy, a cyano, a nitro, an amino free or substituted by one or two (C 1 -C 7 ) alkyls, said substituents being identical or different.
• - A is an amon
• the radical Ar may be a phenyl group, which may be unsubstituted or optionally contain one or more substituents.
• Ar is a phenyl group
• this can be mono or disubstituted in particular in position 2,4 but also for example in position 2, 3, 4, 5, 3, 4, or 3,
• the radical Ar can also represent a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl, one or more bonds of which may be hydrogenated, said groups possibly being unsubstituted or optionally containing one or more substituents such as: alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino and alkoxycarbonyl, thioalkyl, halogen, alkoxy, trifluoromethyl group, in which the alkyls are C 1 -C 4 .
• a bicyclic aromatic group such as 1- or 2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-indenyl, one or more bonds of which may be hydrogenated, said groups possibly being unsubstituted or optionally containing one or more substituents such as: alkyl, phenyl, cyano, hydroxyalky
• the radical Ar may also be a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofurannyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzoxoxylyl, benzoxoxylyl, benzoxoxyl) furyle, pyrannyle, ehromenyle, isobenzofurannyle, pyrrolyle, pyrazolyle, pyrazinyle, pyrimidinyle, pyridazinyle, indolizinyle, phtalazinyle, quinazolinyle, acridinyle, isothiazolyle, isochromannyle, chromannyle, carboxyaryl, of which one or more non-substituted groups can be non-sub
• a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C 1 -C 4 ) alkyl; a benzylamino; carboxy; a (C 1 -C 10 ) alkyl; a (C 3 -C 8 ) cycloalkyl which is unsubstituted or substituted one or more times with methyl; a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C 1 -C 4 ) alkyl; a benzylamino; carboxy; a (C 1 -C 10 ) alkyl; a (C 3 -C 8 )
• the invention relates to the compounds of formula (I) in which:
• a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C 1 -C 4 ) alkyl; a benzylamino; carboxy; a (C 1 -C 10 ) alkyl; a (C 3 -C 8 ) cycloalkyl which is unsubstituted or substituted one or more times with methyl; a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C 1 -C 4 ) alkyl; a benzylamino; carboxy; a (C 1 -C 10 ) alkyl; a (C 3 -C 8 )
• - T represents a direct bond; a hydroxymethylene group; an (C 1 -C 4 ) alkoxymethylene group; a (C 1 -C 5 ) alkylene group; an oxygen atom; a group -NR 3 -; vinylene;
• - Ar represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a trifluoromethyl, a hydroxy, a (C 1 -C 4 ) alkoxy, a (C 1 -C 4 ) alkyl, said substituents being identical or different; thienyl; benzothienyl; naphthyl; an indolyl optionally N-substituted by a (C 1 -C 4 ) alkyl or a benzyl;
• R 1 represents a hydrogen; a (C 1 -C 4 ) alkyl; ⁇ -hydroxy- (C 2 -C 4 ) alkylene; ⁇ - (C 1 -C 4 ) alkoxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) (C 2 -C 4 ) alkylcarbonyloxyalkylene; a ⁇ -benzoyloxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkylthio- (C 2 -C 4 ) alkylene; ⁇ -carboxy- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkoxycarbonyl- (C 2 -C 4 ) alkylene; a ⁇ - (C 1 -C 4 ) alkylcarbonyl- (C 2 -C 4 ) alkylene;
• R 2 represents hydrogen; - or else R 1 and R 2 , together, form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
• R 3 represents a hydrogen or a (C 1 -C 4 ) alkyl
• R 4 represents a group
• - W represents a direct bond; a methylene group; an oxygen atom; a sulfur atom; a group -NR 3 -;
• R5 represents a hydrogen; halogen; hydroxy; a (C 1 -C 4 ) alkoxy; a (C 1 -C 4 ) alkyl; trifluoromethyl;
• the compounds of formula (I) according to the invention include both optically pure isomers and racemates.
• salts of the compounds of formula can be formed
• salts also include those with mineral or organic acids which allow proper separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic acid or camphorsulfonic, than those who form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methanesulfonate, the methyl sulfate, the maleate, the fumarate, the 2-naphthalenesulfonate, the benzenesulfonate, the glyconate, the gluconate, the citrate, isethionate, paratoluenesulfonate.
• mineral or organic acids which allow proper separation or crystallization of the compounds of formula (I)
• such as picric acid or oxalic acid or an optically active acid for example a mandelic acid or camphorsulfonic
• the anions are those normally used to salify the quaternary ammonium ions, preferably the chloride, bromide, iodide, acetate, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, benzenesulfonate ions.
• alkyl groups or the alkoxy groups are straight or branched;
• halogen atom means a chlorine, bromine, fluorine or iodine atom.
• (C 1 -C 10 ) alkyl is meant for example a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, a tert- butyl, pentyl or n-pentyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-nonyl, decyl or n-decyl; by (C 3 -C 8 ) cycloalkyl optionally substituted by a methyl is understood for example to mean a cyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopentyl, a cyclohexyl,
• the radical Ar represents a phenyl which is unsubstituted or substituted one or more times by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C 1 -C 4 ) alkyl, hydroxy, (C 1 -C 4 ) alkoxy; naphthyl unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a (C 1 -C 4 ) alkyl, a hydroxy, a (C 1 -C 4 ) alkoxy; pyridyl; thienyl; indolyl; quinolyl; benzothienyl; an imidazolyl. More particularly, the radical Ar is a phenyl group substituted with an isopropoxy group, advantageously in position 3.
• T preferably represents a methylene group.
• R 1 and R 2 are preferably respectively a methyl group and hydrogen; a 2-methoxyethyl group and hydrogen; 2acetoxyethyl group and hydrogen; a 2-hydroxyethyl group and hydrogen; or Rj and R 2 together form a 1,3-propylene group.
• the substituent Ar ′ is preferably a phenyl group, advantageously substituted by two chlorine atoms or two fluorine atoms, more particularly in positions 3 and 4.
• the substituent Am ⁇ in formula (I) is preferably the substituted 1-pyridylium radical:
• R 4 is preferably an unsubstituted phenyl group or an unsubstituted benzyl group.
• -Ar is a 3-isopropoxyphenyl group
• -T is a methylene group
• -R 1 and R 2 are, respectively, a methyl group and hydrogen; a 2-acetoxyethyl group and hydrogen; a 2-hydroxyethyl group and hydrogen; or, together, form a 1,3-propylene group;
• -Ar is 3,4-dichlorophenyl or 3,4-difluorophenyl
• -Am ⁇ is a 1-pyridylium radical substituted in position 4 by a phenyl or a benzyl
• -A ⁇ is a pharmaceutically acceptable anion.
• iPr represents the isopropyl radical
• Ar represents 3,4-dichlorophenyl or 3,4-difluorophenyl
• R ' 1 and R' 2 represent, respectively, a methyl group and hydrogen, a 2-acetoxyethyl group and hydrogen, a group 2- hydroxyethyl and hydrogen, or together form a 1,3-propylene group
• R ' 4 is a phenyl or benzyl group and
• a ⁇ is a pharmaceutically acceptable anion
• A is a pharmaceutically acceptable anion
• the pharmaceutically acceptable anions of compounds I ', I "and I"' are chosen from chloride, bromide, iodide, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, acetate, benzenesulfonate ions.
• the present invention relates to a process for the preparation of the compounds of formula (I) above, characterized in that a derivative of formula is treated:
• Y represents a methyl group, phenyl, tolyl, trifluoromethyl and Ar
• m, T, R 1 , R 2 and Ar 1 are as defined above for (I), it being understood that when R 1 represents a group ⁇ -hydroxy- (C 2 -C 4 ) alkylene, the hydroxyl is protected, and when R 1 represents a ⁇ -amino- (C 2 - C 4 ) alkylene group, the amino is protected, with an aromatic heterocycle of formula :
• a polar aprotic solvent is preferably used, for example acetonitrile, N, N-dimethylformamide, N, N-dimethylphenylacetamide, but an ether can also be used, for example tetrahydrofuran, dioxane, methyl -ferf-butyl ether, or a ketone, for example methyl ethyl ketone, acetonitrile being particularly preferred.
• the preferred temperature is 70-90oC.
• acetonitrile it is advantageous to operate at reflux of the reaction mixture.
• the O-protecting groups used to obtain a compound of formula (I) in which R 1 represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene are the O- groups conventional protectors well known to those skilled in the art such as, for example, acetyl or benzoyl.
• N-protecting groups used to obtain a compound of formula (I) in which R 1 represents a ⁇ -amino- (C 2 -C 4 ) alkylene are the conventional N-protecting groups well known to those skilled in the art such as, for example, tert-butoxycarbonyl.
• the compound of formula (I) obtained represents the final product in which Ri represents a ⁇ -acetoxy- (C 2 -C 4 ) alkylene or a ⁇ -benzoyloxy- (C 2 -C 4 ) alkylene.
• the compounds of formula (I) thus obtained are hydrolysed according to the usual methods, to obtain the compounds of formula (I) in which Ri represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene.
• the compound of formula (I) obtained represents the final product in which R 1 represents a ⁇ -R 13 group OCONR 12 - (C 2 -C 4 ) alkylene in which R 13 represents the tert-butyl radical.
• the product thus obtained is isolated according to the usual techniques, for example, by concentration of the solvents then washing of the residue with diethyl ether followed by purification according to conventional techniques, for example by chromatography or recrystallization.
• the sulfonate anion YSO 3 ⁇ resulting from the reaction between the aromatic heterocyclic of formula (III) and the derivative of formula (II) can be exchanged, in situ or after isolation of the compound (I) in which A ⁇ is the ion YSO 3 ⁇ by another anion A ⁇ , according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or with a hydrochloric acid solution when A represents a chloride anion or by exchange of anion by elution of the compound (I) on an ion exchange resin, for example Amberlite IRA68 or Duolite A375.
• Amberlite IRA68 Amberlite IRA68 or Duolite A375.
• T represents in the formulas indicated in DIAGRAM 1 a direct bond or a hydroxymethylene group or a (C 1 -C 4 ) alkoxymethylene group or a (C 1 -C 5 ) alkylene group or a vinylene group.
• R ' 3 represents in the formulas indicated in DIAGRAM 1 a (C 1 - C 4 ) alkyl.
• DIAGRAM 1 the reactions in the different stages are indicated in a representative manner in order to indicate the type of said reactions, the means of which are known.
• Stage 1 of SCHEMA 1 is described in patent applications EP-A-0428434 and EP-A-0474561.
• step 6 H 2 " means that the starting nitrile is subjected to reduction, for example to catalytic hydrogenation (Ni-Raney in ethanol in the presence of ammonia).
• alkylation means that after the reduction, the primary amine is subjected to an alkylation reaction to introduce the radical R ' 1 other than H.
• R' 1 is a C 1 -C 4 alkyl
• the alkylation is carried out either directly with an alkyl halide or sulphate, or indirectly, by acylation and reduction of the carbonyl group.
• R ′ 1 is methyl as described in EP-A-0428434 and EP-A -0474561.
• the ethyl chloroformate can be replaced by di-tert-butyldicarbonate to prepare the process of formula (IV) where R ' 1 is methyl. Furthermore, by replacing ethyl chloroformate with chloride (or another functional derivative) of a C 2 -C 4 alkanoic acid and by reduction of the carbonyl group of the N-acylated derivative thus obtained, the compound of formula (IV) where R ' 1 is C 2 -C 4 alkyl.
• the reduction is carried out in a solvent such as tetrahydrofuran or toluene at a temperature between 0oC and 70oC.
• a solvent such as tetrahydrofuran or toluene
• step 3 ca Route A the compound (IV) can be coupled with an acid of formula Ar- 3 "-COOH according to the conventional methods of peptide synthesis, when T represents a direct bond or a hydroxymethylene group or a group ( C 1 -C 4 ) alkoxymethylene or a C 1 -C 5 alkylene group or a vinylene group
• T represents a direct bond or a hydroxymethylene group or a group ( C 1 -C 4 ) alkoxymethylene or a C 1 -C 5 alkylene group or a vinylene group
• functional derivatives of this acid which react with amines, for example an anhydride, a mixed anhydride, chloride d acid or an activated ester, such as the paranitrophenyl ester.
• the operation is carried out in the presence of a coupling agent used in peptide chemistry such as benzotriazol 1,3-dicyclohexylca ⁇ bodiimide or hexafluorophosphate- 1-yloxytris (dimethylamino) phosphonium in the presence of a base such as triethylamine or N, N-diisopropylethylamine, in an inert solvent such as dichloromethane or N, N-dimethylformamide at a temperature between 0 ° C and ambient temperature.
• a coupling agent used in peptide chemistry such as benzotriazol 1,3-dicyclohexylca ⁇ bodiimide or hexafluorophosphate- 1-yloxytris (dimethylamino) phosphonium
• a base such as triethylamine or N, N-diisopropylethylamine
• an inert solvent such as dichloromethane or N,
• the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine and at a temperature between - 70oC and room temperature.
• an inert solvent such as dichloromethane or benzene
• a base such as triethylamine or N-methylmorpholine
• T represents an oxygen atom
• the reaction of the compound of formula (TV) with a chloroformate of formula Ar-O-CO-Cl, in a solvent such as dichloromethane, is used at a temperature between 0oC and the temperature ambient and in the presence of a base such as triethylamine.
• T represents a group -NR 3 - in which R 3 represents hydrogen
• T represents a group -NR 3 - in which R 3 represents a C 1 -C 4 alkyl
• the reaction of the compound of formula (IV) with a carbamoyl chloride of formula Ar-NR ' 3 -CO-Cl is used in which R ' 3 represents a C 1 -C 4 alkyl, in a solvent such as toluene or 1,2-dichloroethane, at a temperature between 80 and 110oC and in the presence of a base such as triethylamine.
• the compound thus obtained is subjected to a subsequent treatment to prepare a compound of formula (IVa) by transformation of the group R ′ 1 into R 1, it being understood that when T represents a hydroxymethylene group , hydroxyl can be protected.
• R ' 1 represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene
• R ' 1 represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene
• the hydroxyl is protected or optionally an O-acylation reaction is carried out according to the methods known to those skilled in the art , to obtain a compound of formula (IVa) in which R 1 represents a ⁇ - (C 1 -C 4 ) alkylcarbonyloxy- (C 2 -C 4 ) alkylene or a ⁇ -benzoyloxy- (C 2 -C 4 ) alkylene.
• a compound of formula (IVa) in which R 1 represents a ⁇ -R 9 R 10 N- (C 2 -C 4 ) alkylene can be prepared by following the various steps of the process described in SCHEME 2.
• step 4 of Route A the tetrahydropyran-2-yl group is removed from the compound of formula (IVa) according to methods known to those skilled in the art, in particular by acid hydrolysis.
• Route B of SCHEME 1 implements a succession of reactions well known to those skilled in the art such as ⁇ -alkylation of a nitrile by a bromine derivative in the presence of lithium diisopropylamide (LDA) (step 5), followed by reduction of the nitrile by hydrogenation in the presence of a catalyst to obtain the compound (V) according to, for example, AV El'tsov et al., Biol. Aktivn. Soedin., Akad.
• LDA lithium diisopropylamide
• the derivative (II) is prepared by reaction of the alcohol (VI) with a Y-SO 2 -CI derivative, for example methanesulfonyl chloride or benzenesulfonyl chloride (step 9) being understood that when in the compound of formula
• R 1 represents a ⁇ -hydroxy- (C 2 -C 4 ) alkylene, the hydroxyl is protected and when R 1 represents a ⁇ -amino- (C 2 -C 4 ) alkylene, the amino is protected .
• the nitrogen aromatic heterocycles of formula (III) are known or prepared by known methods.
• the compound (VII *) obtained after the separation of the enantiomers of (VII) and after a step of protecting the hydroxyl function, for example by reaction with 3,4-dihydro-2H-pyran, is subjected to a step of substitution of the amine function to induce the group R ' 1 according to the procedures described to prepare the compounds of formula (IV).
• the compound thus obtained is subjected to a subsequent treatment to prepare a compound of formula (IV * a ) by transformation of the group R ′ 1 into R 1 according to the methods described above.
• the pure diastereoisomers and isomers can be prepared by reaction of the optically pure amino alcohol (VII *) or (VIII *) and of HO-CO-T "-Ar acid, either optically pure or racemic in which T "represents a hydroxymethylene group or a C 1 -C 4 alkoxymethylene group and, in the latter case, the diastereoisomers can be separated, for example by chromatography.
• the compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium, carbon-14 or iodine-125.
• radioactive isotope for example tritium, carbon-14 or iodine-125.
• the compounds according to the invention exhibit an affinity for the tachykinin receptors mentioned above, with an inhibition constant Ki of less than 10 -8 M.
• the compounds of formula (I) above can be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 50 mg / kg.
• the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment: prophylactic or curative .
• the compounds of formula (I) are generally administered in dosage units.
• Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
• the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I).
• the active ingredients can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, animals and humans.
• Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants, forms subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.
• the main active principle is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or analogues.
• a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or analogues.
• the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
• a preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
• a preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
• a sweetener preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
• the water-dispersible powders or granules may contain the active principle in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpy ⁇ olidone, as well as with sweeteners or taste.
• Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
• aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
• an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoromethane or any other biologically compatible propellant is used; one can also use a system comprising the active principle, alone or associated with an excipient, in powder form.
• the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
• each dosage unit the active principle of formula (I) is present in the quantities adapted to the daily doses envisaged.
• each dosage unit is suitably adjusted according to, the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains from 0.5 to 1000 mg of active principle, preferably from 2.5 to 250 mg to be administered one to four times a day.
• the present invention relates to the use of the products of formula (I) for the preparation of medicaments intended to treat physiological disorders associated with an excess of tachykinins, in particular of Substance P and all tachykinin-dependent pathologies respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous systems as well as pain and migraine.
• inflammations such as chronic obstructive respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity for example to pollens and mites, rheumatoid arthritis, osteoarthritis, psoriasis, costs ulcers, Crohn's disease, inflammation of the intestines (irritable colon), prostatitis, neurological bladder, cystitis, urethritis, nephritis,
• neurodegenerative diseases of the central nervous system of the neuropsychiatric or neurological type such as anxiety, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drugs -dependence, Down syndrome and Huntington's chorea as well as neurodegenerative diseases,
• vascular aspects of migraine, edema, thrombosis, angina pectoris, vascular spasms and hypertension such as vascular aspects of migraine, edema, thrombosis, angina pectoris, vascular spasms and hypertension.
• the present invention also includes a method for treating said conditions at the doses indicated above.
• a suspension of 0.9 g of aluminum hydride and lithium in 5 ml of THF is heated to 60 ° C., a solution of 3.9 g of the compound obtained in the previous step in 50 ml of THF is added and 1 hour with stirring at 60oC. After cooling, 1 ml of water, 1 ml of 4N NaOH and 3 ml of water are added. The mineral salts are filtered on Celite, the filtrate is decanted, and the organic phase is evaporated under vacuum. The residue is taken up in ether, dried over magnesium sulfate and the solvent is evaporated under vacuum. 3.4 g of the expected product are obtained, which product is used as it is in the next step.

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• General Health & Medical Sciences (AREA)
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• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• Biomedical Technology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 1994
  • 1994-03-25 FR FR9403561A patent/FR2717804B1/fr not_active Expired - Fee Related
• 1995
  • 1995-03-24 HU HU9503377A patent/HU216843B/hu not_active IP Right Cessation
  • 1995-03-24 AU AU21421/95A patent/AU2142195A/en not_active Abandoned
  • 1995-03-24 WO PCT/FR1995/000368 patent/WO1995026339A1/fr not_active Application Discontinuation
  • 1995-03-24 EP EP95914414A patent/EP0700387A1/de not_active Withdrawn
  • 1995-03-24 JP JP7525002A patent/JPH08511276A/ja active Pending
  • 1995-03-24 US US08/545,772 patent/US5665886A/en not_active Expired - Fee Related

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